The Role of Hedgehog Signalling in the Formation of the Ventricular Septum

Abstract

An incomplete septation of the ventricles in the vertebrate heart that disturbes the strict separation between the contents of the two ventricles is termed a ventricular septal defect (VSD). Together with bicuspid aortic valves, it is the most frequent congenital heart disease in humans. Until now, life-threatening VSDs are usually treated surgically. To avoid surgery and to develop an alternative therapy (e.g., a small molecule therapy), it is necessary to understand the molecular mechanisms underlying ventricular septum (VS) development. Consequently, various studies focus on the investigation of signalling pathways, which play essential roles in the formation of the VS. In the past decade, several reports found evidence for an involvement of Hedgehog (HH) signalling in VS development. In this review article, we will summarise the current knowledge about the association between HH signalling and VS formation and discuss the use of such knowledge to design treatment strategies against the development of VSDs.

Keywords: Down syndrome; GSA-10; SAG; SMO; Smoothened; VSD; cilia; oxysterols; purmorphamine; ventricular septal defect.

Figure 1

Development of the ventricular septum. (A) The linear heart tube balloons to give rise to precursor structures of the heart chambers. (B) The heart takes its four-chambered shape by a process termed heart looping. (C) Proliferating cells (in purple) of the ventricular walls lead to the outgrowth of the muscular ventricular septum (in dark blue). (D) In addition, trabeculae that are derived from the ventricular walls start to participate in the formation of the ventricular septum. (E) After a molecular interaction between the muscular ventricular septum and the endocardial cushion cells (in bright blue), the membranous ventricular septum develops from the endocardial cushion cells and grows towards the muscular ventricular septum. (F) Finally, the muscular and membranous ventricular septa fuse. (G) The atrioventricular endocardial cushion cells give rise to the atrioventricular valves. LA, left atrium; LV, left ventricle; OFT, outflow tract; RA, right atrium; RV, right ventricle.

Figure 2

Hedgehog signalling at primary cilia.